The mucopolysaccharidoses (MPS) represent a group of rare, inherited lysosomal storage disorders caused by the deficiency or inactivity of lysosomal enzymes. In particular, the MPS disorders are caused by the deficiency or inactivity of the lysosomal enzymes which catalyze the stepwise metabolism of complex sugar molecules known as glycosaminoglycans (GAGs). These enzyme deficiencies in turn result in the accumulation of GAGs in the cells, tissues, and, in particular, cellular lysosomes of affected subjects, resulting in permanent, progressive cellular damage which affects appearance, physical abilities, organ and system functioning, and, in most cases, mental development of affected subjects.
Eleven discrete enzyme deficiencies have been identified, which result in seven distinct clinical classes of MPS. Each MPS disorder is characterized by a deficiency or inactivity of an enzyme involved in the metabolism of one or more of the GAGS heparan sulfate (HS), dermatan sulfate (DS), chondroitin sulfate (CS), keratan sulfate (KS) or hyaluronan. As a result, such GAGs accumulate in the cells and tissues of affected subjects.
The diagnosis of MPS and the monitoring of both disease progression and treatment efficacy rely on subjective and objective monitoring of the subject. Available objective assays useful for the diagnosis of MPS and for monitoring treatment efficacy have traditionally lacked sensitivity, have significant limitations, and have been characterized as inadequate (see for example, Oguma T, et al., Analytical Biochemistry (2007) 368: 79-86.)
Diagnosis of MPS can be made through urinalysis. For example, the use of diagnostic methods which rely on spectrophotometry to measure total GAGs in urine are based upon binding to dimethylmethylene blue, and are limited to use in urinary assays. Furthermore, the utility of urinalysis determinations, may not be indicative of a specific MPS disorder because the presence of excess GAGs in the urine of a subject may only provide objective evidence that either one of the several MPS disorders are present. (Neufeld E F, et al., The mucopolysaccharidoses. In: Scriver CR, ed. The Metabolic and Molecular Bases of Inherited Disease. New York, N.Y.: McGraw-Hill (2001) 3421-3452.) Similarly, urinalysis assays which analyze GAGs content in the urine are not particularly sensitive and a negative urine GAGs test may not necessarily preclude a diagnosis of MPS. Reported assays based on the use of enzymatic digestion of GAGs and high-performance liquid chromatography (HPLC) detection of the corresponding disaccharides are also limited, for example due to their lack of specificity and/or sensitivity.
Reported assays which measure biological markers correlating to MPS also have limitations. For example, assays which measure serum levels of a heparin cofactor-II-thrombin complex (THC) have been described as a monitoring tool for subjects with MPS. (Randall, D R, et al. Molecular Genetics and Metabolism (2008), 94: 456-461.) Such assays however, are of limited use in MPS classes where the accumulating pathological GAG is not primarily dermatan sulfate, such as in MPS-III, MPS-IV, MPS-VII or MPS-IX, since under physiological conditions formation of THC is not efficiently catalyzed by HS, CS, KS or hyaluronan.
New screening methods, assays and biological markers are needed to diagnosis MPS and to monitor clinical course and disease progression/regression before, during and after treatment. In particular new assays that are useful for quantifying GAGs in a variety of biological samples (e.g., serum, urine, and CSF) would be useful to monitor disease severity, progression and treatment efficacy.